A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse
0301 basic medicine
Proline
Molecular Sequence Data
TRPM Cation Channels
Apoptosis
Protein Structure, Secondary
Cell Line
Protein Structure, Tertiary
Mice
03 medical and health sciences
Transient Receptor Potential Channels
Amino Acid Substitution
Animals
Amino Acid Sequence
Hearing Loss
DOI:
10.1073/pnas.0709846104
Publication Date:
2007-11-29T01:45:29Z
AUTHORS (8)
ABSTRACT
Homozygote varitint-waddler (
Va
) mice, expressing a mutant isoform (A419P) of TRPML3 (mucolipin 3), are profoundly deaf and display vestibular and pigmentation deficiencies, sterility, and perinatal lethality. Here we show that the varitint-waddler isoform of TRPML3 carrying an A419P mutation represents a constitutively active cation channel that can also be identified in native varitint-waddler hair cells as a distinct inwardly rectifying current. We hypothesize that the constitutive activation of TRPML3 occurs as a result of a helix-breaking proline substitution in transmembrane-spanning domain 5 (TM5). A proline substitution scan demonstrated that the inner third of TRPML3's TM5 is highly susceptible to proline-based kinks. Proline substitutions in TM5 of other TRP channels revealed that TRPML1, TRPML2, TRPV5, and TRPV6 display a similar susceptibility at comparable positions, whereas other TRP channels were not affected. We conclude that the molecular basis for deafness in the varitint-waddler mouse is the result of hair cell death caused by constitutive TRPML3 activity. To our knowledge, our study provides the first direct mechanistic link of a mutation in a TRP ion channel with mammalian hearing loss.
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CITATIONS (139)
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